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The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin

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Abstract

Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6 weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.

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Abbreviations

TAA:

Thioacetamide

SGZ:

Saroglitazar

PPAR:

Peroxisome proliferator-activated receptor

TGF-β1:

Transforming growth factor-β1

α-SMA:

Alpha-smooth muscle actin

PDGF-BB:

Platelet-derived growth factor-BB

TIMP-1:

Tissue inhibitor of metalloproteinases-1

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Acknowledgments

The authors acknowledge Dr. Walied Abdo, Associate Prof. of Veterinary Pathology, Kafr El Sheikh University, Egypt, for aiding in the histopathological examination.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Mirhan N. Makled, Maha H. Sharawy & Mohammed S. El-Awady

Authors
  1. Mirhan N. Makled
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  2. Maha H. Sharawy
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  3. Mohammed S. El-Awady
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Contributions

All authors contributed equally. MM, MS, and ME conceived, designed the research, conducted the experiments, analyzed the data, and wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Maha H. Sharawy.

Ethics declarations

Animal welfare was ensured in accordance with the ethical standards of the “Research Ethics Committee” of the Faculty of Pharmacy, Mansoura University, Egypt, code number (2017-101/2019-20). These institutional standards are in line with “Principles of laboratory Animal Care” (NIH publication No. 85-23, revised 1985).

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The authors declare that they have no conflict of interest.

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Makled, M.N., Sharawy, M.H. & El-Awady, M.S. The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1569–1576 (2019). https://doi.org/10.1007/s00210-019-01703-5

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  • DOI: https://doi.org/10.1007/s00210-019-01703-5

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